JP6473352B2 - Drug for ischemic disease - Google Patents
Drug for ischemic disease Download PDFInfo
- Publication number
- JP6473352B2 JP6473352B2 JP2015046825A JP2015046825A JP6473352B2 JP 6473352 B2 JP6473352 B2 JP 6473352B2 JP 2015046825 A JP2015046825 A JP 2015046825A JP 2015046825 A JP2015046825 A JP 2015046825A JP 6473352 B2 JP6473352 B2 JP 6473352B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- halogen atom
- solvent
- represented
- coo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Description
本発明は、新規化合物及び前記化合物を含む医薬組成物に関する。 The present invention relates to a novel compound and a pharmaceutical composition comprising the compound.
また、本発明は、虚血性疾患治療薬に関する。 The present invention also relates to a therapeutic agent for ischemic diseases.
心筋梗塞、脳梗塞は、虚血再灌流障害の代表的な疾患であり、血管の一時的又は持続的な閉塞もしくは急激な血流減少により心筋細胞、神経細胞などの細胞の虚血性壊死を生じて心臓、脳などの臓器、組織に障害、機能低下をもたらす。虚血性疾患の直接的原因は、動脈硬化や動脈もしくは静脈内の血栓形成による血流減少又は停止である。 Myocardial infarction and cerebral infarction are typical diseases of ischemia-reperfusion injury, and arechemic necrosis of cells such as myocardial cells and nerve cells is caused by temporary or continuous occlusion of blood vessels or rapid blood flow reduction. Cause damage to organs and tissues such as the heart and brain, and functional deterioration. The direct cause of ischemic disease is decreased or stopped blood flow due to arteriosclerosis or thrombus formation in the artery or vein.
虚血性疾患の治療においては、閉塞した動脈又は静脈を血管内挿入バルーンにより拡張させたり、ステントを血管内に挿入することにより血流を確保したり、血管内に生じた血栓を血栓溶解剤により溶解除去する方法が採用されている。このような治療においては、冠状動脈内に血流が再開されるに伴いＣａ過負荷やフリーラジカルが発生し、細胞の壊死領域が広がることが知られているが、このような虚血再灌流障害の発生を予防するのは困難であり、有効な治療方法が定まっていないのが現状である。 In the treatment of ischemic disease, a blocked artery or vein is expanded by an intravascular balloon, a blood flow is secured by inserting a stent into the blood vessel, or a thrombus generated in the blood vessel is treated with a thrombolytic agent. A method of dissolving and removing is employed. In such treatment, it is known that Ca overload and free radicals are generated as the blood flow is resumed in the coronary artery, and the necrotic region of the cell is expanded. It is difficult to prevent the occurrence of disability, and the current situation is that no effective treatment method has been established.
代表的な虚血性疾患である虚血性心疾患を治療する方法として遺伝子導入を行う方法（特許文献１）が知られている。 As a method for treating ischemic heart disease, which is a typical ischemic disease, a method of gene transfer (Patent Document 1) is known.
本発明は、虚血再灌流障害を治療することができる化合物及び医薬組成物を提供することを目的とする。 An object of the present invention is to provide a compound and a pharmaceutical composition capable of treating ischemia-reperfusion injury.
本発明は、以下の化合物、医薬組成物及び虚血性疾患治療薬を提供するものである。
項１． 下記式（I）で表される化合物
The present invention provides the following compounds, pharmaceutical compositions and therapeutic agents for ischemic diseases.
Item 1. Compound represented by the following formula (I)
（式中、Ｒ１は同一又は異なってハロゲン原子、ハロゲン原子で置換されていてもよいメチル基を示す。Ｒ２は水素原子又はハロゲン原子を示す。Ｒ３はＣＯＯ−、ＰＯ(ＯＨ) (Ｏ−)又はＳＯ３ −を示す。Ｙは−ＣＯＯ−、−ＣＯＮＨ−又は−ＳＯ２ＮＨ−である。）
又はその塩。
項２． 下記式（ＩＡ）
(In the formula, R 1 is the same or different and represents a halogen atom or a methyl group which may be substituted with a halogen atom. R 2 represents a hydrogen atom or a halogen atom. R 3 represents COO − , PO (OH) ( O -) or SO 3 - are shown .Y is -COO -, - CONH- or -SO 2 NH-).
Or a salt thereof.
Item 2. The following formula (IA)
（式中、Ｒ１は同一又は異なってハロゲン原子、ハロゲン原子で置換されていてもよいメチル基を示す。Ｒ２は水素原子又はハロゲン原子を示す。Ｒ３はＣＯＯ−、ＰＯ(ＯＨ) (Ｏ−)又はＳＯ３ −を示す。）
で表される項１に記載の化合物又はその塩。
項３． 下記式（ＩＢ）
(In the formula, R 1 is the same or different and represents a halogen atom or a methyl group which may be substituted with a halogen atom. R 2 represents a hydrogen atom or a halogen atom. R 3 represents COO − , PO (OH) ( O -) or SO 3 - shows a).
The compound or its salt of claim | item 1 represented by these.
Item 3. The following formula (IB)
（式中、Ｒ１は同一又は異なってハロゲン原子、ハロゲン原子で置換されていてもよいメチル基を示す。）
で表される項１又は２に記載の化合物又はその塩。
項４． 下記式
(In the formula, R 1 is the same or different and represents a halogen atom or a methyl group which may be substituted with a halogen atom.)
The compound or its salt of claim | item 1 or 2 represented by these.
Item 4. Following formula
で表される、項１〜３のいずれかに記載の化合物又はその塩。 The compound or its salt in any one of claim | item 1-3 represented by these.
項５． 項１〜４のいずれかに記載の化合物を含む医薬組成物
項６． 項１〜４のいずれかに記載の化合物を含む虚血性疾患治療薬。
項７． 虚血性疾患が、虚血再灌流障害、心筋梗塞、脳梗塞、遠隔臓器障害又は腸間膜血管閉塞症である、項６に記載の虚血性疾患治療薬。
Item 5. Item 5. A pharmaceutical composition comprising the compound according to any one of Items 1 to 4. Item 5. A therapeutic agent for ischemic disease comprising the compound according to any one of Items 1 to 4.
Item 7. Item 7. The therapeutic agent for ischemic disease according to item 6, wherein the ischemic disease is ischemia / reperfusion injury, myocardial infarction, cerebral infarction, distant organ injury or mesenteric vascular occlusion.
本発明によれば、虚血後再灌流時の障害を抑制し、虚血臓器の機能を回復することができる。 ADVANTAGE OF THE INVENTION According to this invention, the disorder | damage | failure at the time of reperfusion after ischemia can be suppressed and the function of an ischemic organ can be recovered | restored.
本明細書において、ハロゲン原子としてはＦ，Ｃｌ，Ｂｒ，Ｉが挙げられる。 In the present specification, examples of the halogen atom include F, Cl, Br, and I.
ハロゲン原子で置換されていてもよいメチル基としては、ＣＨ３，ＣＨ２Ｆ，ＣＨＦ２，ＣＦ３，ＣＨ２Ｃｌ、ＣＨＣｌ２，ＣＣｌ３が挙げられる。 Examples of the methyl group which may be substituted with a halogen atom include CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 Cl, CHCl 2 and CCl 3 .
Ｒ１はハロゲン原子又はハロゲン原子で置換されていてもよいメチル基を示し、好ましくはハロゲン原子又はメチル基、より好ましくはハロゲン原子、さらに好ましくはＣｌを示す。 R 1 represents a halogen atom or a methyl group which may be substituted with a halogen atom, preferably a halogen atom or a methyl group, more preferably a halogen atom, still more preferably Cl.
Ｒ２は水素原子又はハロゲン原子を示し、好ましくは水素原子を示す。 R 2 represents a hydrogen atom or a halogen atom, preferably a hydrogen atom.
Ｒ３は酸性基を表し、具体的にはＣＯＯ−、ＰＯ(ＯＨ) (Ｏ−)又はＳＯ３ −を示し、好ましくはＣＯＯ−、ＳＯ３ −、さらに好ましくはＳＯ３ −である。 R 3 represents an acidic group, specifically represents COO − , PO (OH) (O − ) or SO 3 — , preferably COO − , SO 3 − , more preferably SO 3 — .
Ｙは二価の連結基を示し、具体的にはＹは−ＣＯＯ−、−ＣＯＮＨ−又は−ＳＯ２ＮＨ−が挙げられ、好ましくは−ＣＯＯ−、−ＳＯ２ＮＨ−が挙げられ、より好ましくは−ＣＯＯ−である。Ｙが−ＣＯＯ−の場合、 式（ＩＡ）又は（ＩＢ）に示すような構造になる。 Y represents a divalent linking group, the Y Specifically -COO -, - CONH- or -SO 2 NH- can be mentioned, preferably -COO -, - SO 2 NH- and the like, more preferably Is —COO—. When Y is —COO—, the structure is as shown in formula (IA) or (IB).
本発明の式（Ｉ）の化合物は、アンモニウムカチオンとＲ３で表されるアニオンとの両性イオン構造を取る。式（Ｉ）の化合物の酸付加塩では、Ｒ３はＨが付加されてＣＯＯＨ、ＰＯ(ＯＨ)２又はＳＯ３Ｈになる。また、酸付加塩では、Ｘ−で表されるカウンターイオンが付加される。カウンターイオンとしては、Ｃｌ−、Ｂｒ−、Ｉ−、１／２ＳＯ４ ２−、ＨＳＯ４ −、硝酸イオン、メタンスルホン酸イオン、ｐ−トルエンスルホン酸イオンが挙げられ、塩を形成する酸としては、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸などの無機酸、メタンスルホン酸、トルエンスルホン酸などの有機酸が挙げられる。 The compound of the formula (I) of the present invention takes a zwitterionic structure of an ammonium cation and an anion represented by R 3 . In the acid addition salt of the compound of formula (I), R 3 is H-added to COOH, PO (OH) 2 or SO 3 H. Further, the acid addition salts, X - counter ion represented by is added. Examples of the counter ions include Cl − , Br − , I − , 1 / 2SO 4 2− , HSO 4 − , nitrate ions, methanesulfonate ions, and p-toluenesulfonate ions. And inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and nitric acid, and organic acids such as methanesulfonic acid and toluenesulfonic acid.
本発明の好ましい化合物(両性イオン構造)を以下に示す。下記の化合物は、酸付加塩の形態であってもよい。 Preferred compounds (zwitterionic structures) of the present invention are shown below. The following compounds may be in the form of acid addition salts.
本発明の最も好ましい化合物の両性イオン(右)と酸付加塩(左)の構造を以下に示す。 The structures of the zwitterion (right) and the acid addition salt (left) of the most preferred compound of the present invention are shown below.
（Ｘ−は、前記に定義されるとおりである）
上記以外の両性イオンと酸付加塩の関係も同様であり、酸付加塩の場合、Ｒ３で表される基はアニオンではなく、水素原子が付加したものになり、さらにアニオン（Ｘ−）が付加される。
(X − is as defined above)
The relationship between zwitterions other than the above and acid addition salts is also the same. In the case of acid addition salts, the group represented by R 3 is not an anion but a hydrogen atom added thereto, and an anion (X − ) Added.
本発明の化合物は、例えば下記のスキーム１に従い製造することができる。 The compound of this invention can be manufactured according to the following scheme 1, for example.
（Ｒ１，Ｒ２は前記に定義されるとおりである）
化合物（１）１モルに対しＮ−ヒドロキシスクシンイミドを１モルから過剰量、ジシクロヘキシルカルボジイミド（ＤＣＣ）などの縮合剤を１モルから過剰量使用し、塩化メチレン、クロロホルム、ＤＭＦ、ＴＨＦなどの溶媒中、室温から溶媒の沸騰する温度で１〜１２時間反応させることで化合物（２）を得ることができる。
(R 1 and R 2 are as defined above)
1 mol of N-hydroxysuccinimide to 1 mol of compound (1) and 1 mol to excess of condensing agent such as dicyclohexylcarbodiimide (DCC) are used in a solvent such as methylene chloride, chloroform, DMF, THF, Compound (2) can be obtained by reacting at room temperature to the boiling temperature of the solvent for 1 to 12 hours.
化合物（２）１モルに対しＮａＢＨ4などの還元剤を１当量から過剰量使用し、溶媒中で室温から溶媒の沸騰する温度で１〜１２時間反応させて、化合物（３）を得ることができる。 A compound (3) can be obtained by using a reducing agent such as NaBH 4 in an amount of 1 equivalent to an excess amount per mole of the compound (2) and reacting in a solvent at room temperature to a boiling temperature of the solvent for 1 to 12 hours. it can.
化合物（３）１モルに対しＮ−ヨードスクシンイミドなどのヨウ素化剤を１モルから過剰量使用し、溶媒中で室温から溶媒の沸騰する温度で１〜１２時間反応させて、化合物（４）を得ることができる。 The compound (3) is used in an amount of 1 to 12 moles of an iodinating agent such as N-iodosuccinimide with respect to 1 mole of the compound (3), and is allowed to react in the solvent from room temperature to the boiling temperature of the solvent for 1 to 12 hours. Can be obtained.
化合物（４）１モルに対しトリメチルアミンを１モルから過剰量使用し、溶媒中で室温から溶媒の沸騰する温度で１〜１２時間反応させて、化合物（５）を得ることができる。 The compound (5) can be obtained by using an excess amount of trimethylamine from 1 mol to 1 mol of the compound (4) and reacting in a solvent at room temperature to a boiling temperature of the solvent for 1 to 12 hours.
化合物（５）１モルに対しトリフルオロ酢酸などの酸を触媒量から過剰量使用し、溶媒中で室温から溶媒の沸騰する温度で１〜１２時間反応させて、脱保護された化合物（６）を得ることができる。 Deprotected compound (6) by using a catalytic amount of an excess of acid such as trifluoroacetic acid with respect to 1 mol of compound (5) and reacting in a solvent from room temperature to the boiling temperature of the solvent for 1 to 12 hours. Can be obtained.
化合物（６）１モルに対し化合物（７）を１モル程度使用し、溶媒中で室温から溶媒の沸騰する温度で１〜１２時間反応させて、式（ＩＣ）の化合物を得ることができる。 About 1 mol of the compound (7) is used per 1 mol of the compound (6), and the reaction is carried out in a solvent from room temperature to the boiling temperature of the solvent for 1 to 12 hours to obtain the compound of the formula (IC).
化合物（６）１モルに対し化合物（８）を１モル程度使用し、溶媒中で室温から溶媒の沸騰する温度で１〜１２時間反応させて、式（ＩＤ）の化合物を得ることができる。 About 1 mol of the compound (8) is used per 1 mol of the compound (6), and the reaction is carried out in a solvent at room temperature to the boiling temperature of the solvent for 1 to 12 hours to obtain the compound of the formula (ID).
化合物（９）１モルに対しトリメチルアミンを１モルから過剰量使用し、溶媒中で室温から溶媒の沸騰する温度で１〜１２時間反応させて、化合物（１０）を得ることができる。 Compound (10) can be obtained by using 1 to 12 mol of trimethylamine in an excess amount with respect to 1 mol of compound (9) and reacting at room temperature to the boiling temperature of the solvent in a solvent for 1 to 12 hours.
化合物（１０）１モルに対し化合物（７）を１モル程度使用し、溶媒中で室温から溶媒の沸騰する温度で１〜１２時間反応させて、式（ＩＥ）の化合物を得ることができる。 About 1 mol of the compound (7) is used per 1 mol of the compound (10), and the reaction is carried out in a solvent from room temperature to the boiling temperature of the solvent for 1 to 12 hours to obtain the compound of the formula (IE).
化合物（１１）１モルに対し化合物（７）を１モル程度使用し、溶媒中で室温から溶媒の沸騰する温度で１〜１２時間反応させて、式（ＩＦ）の化合物を得ることができる。 About 1 mol of the compound (7) is used per 1 mol of the compound (11), and the reaction is carried out in a solvent from room temperature to the boiling temperature of the solvent for 1 to 12 hours to obtain the compound of the formula (IF).
化合物（１１）１モルに対し化合物（８）を１モル程度使用し、溶媒中で室温から溶媒の沸騰する温度で１〜１２時間反応させて、式（ＩＧ）の化合物を得ることができる。 About 1 mol of the compound (8) is used per 1 mol of the compound (11), and the reaction is carried out at room temperature to the boiling temperature of the solvent for 1 to 12 hours in the solvent to obtain the compound of the formula (IG).
本発明化合物は、虚血再灌流障害、例えば、心筋梗塞、脳梗塞、腸間膜血管閉塞症などにおける血栓部位をバルーンなどの装置や血栓溶解剤などの医薬を用いて再灌流したときに生じる臓器障害（梗塞／血栓を生じた臓器の障害及び遠隔臓器障害を含む）の予防又は治療薬として有効である。 The compound of the present invention occurs when a thrombus site in ischemia-reperfusion injury such as myocardial infarction, cerebral infarction, mesenteric vascular occlusion is reperfused using a device such as a balloon or a medicine such as a thrombolytic agent. It is effective as a preventive or therapeutic agent for organ damage (including injuries / thrombotic organ damage and distant organ damage).
本発明化合物を有効成分とする医薬は、その使用目的に合わせて投与方法、剤型、投与量を適宜決定することが可能である。例えば、本発明の化合物を有効成分とする医薬の投与形態は、経口投与でも非経口投与でも良い。剤型としては、例えば錠剤、粉剤、カプセル剤、顆粒剤、エキス剤、シロップ剤等の経口投与剤、または注射剤、点滴剤、もしくは坐剤等の非経口投与剤を挙げることができる。これらの製剤は、賦形剤、結合剤等の製薬上許容される添加材を用いて既知の方法で製造することができる。本発明の化合物を有効成分として含む医薬の投与量は、症状、投与対象の年齢、体重、性別等を考慮して個々の場合に応じて適宜決定されるが、通常、成人一日当たり経口投与の場合、0.1-500 mg、非経口投与の場合0.01-100 mg程度が適当であり、これを一日に一回乃至複数回投与する。投与量は種々の条件で変動するので、上記投与量範囲より少ない量で充分な場合もある。 A pharmaceutical comprising the compound of the present invention as an active ingredient can be appropriately determined in administration method, dosage form, and dosage according to the purpose of use. For example, the pharmaceutical dosage form containing the compound of the present invention as an active ingredient may be oral or parenteral. Examples of the dosage form include oral administration agents such as tablets, powders, capsules, granules, extracts and syrups, and parenteral administration agents such as injections, drops, and suppositories. These preparations can be produced by known methods using pharmaceutically acceptable additives such as excipients and binders. The dosage of the pharmaceutical agent containing the compound of the present invention as an active ingredient is appropriately determined depending on the individual case in consideration of symptoms, age, weight, sex, etc. of the subject of administration. In the case of 0.1-500 mg in the case of parenteral administration, about 0.01-100 mg is appropriate, and this is administered once to several times a day. Since the dosage varies depending on various conditions, an amount smaller than the above dosage range may be sufficient.
以下、本発明を実施例及び比較例により詳細に説明する。 Hereinafter, the present invention will be described in detail with reference to Examples and Comparative Examples.
実施例１
（１）虚血再灌流実験
(1-1)使用動物 6週Splague-Dawley ラット
(1-2)孤立心臓灌流システム：全身麻酔後に摘出した心臓の大動脈と左心房にカニューラを挿入後、灌流液を流す。心臓は自動的に拍動し、灌流液を拍出する。その圧力（＝血圧）、心拍数、流量を測定して心機能の指標とする。灌流液を遮断、再開することにより虚血、再灌流の影響を検討した。
(1-3)灌流条件
(i)灌流液：Krebs-Henseleit緩衝液（NaCl;118mM、KCl;4.7mM、KH2PO4;1.2mM、MgSO4・7H2O;1.2mM、CaCl2・2H2O;1.25mM）に5.5mM ブドウ糖、1.2mM パルミチン酸、3%アルブミンを追加したものを用いた。
(ii)灌流液は95% CO2+ 5%O2ガスにより酸素化した。
(iii)前灌流20分→灌流遮断40分→再灌流30分のプロトコルで灌流した。
註1．パルミチン酸を混合するのは、脂肪酸存在下では再灌流時の機能障害が増強することと、心筋梗塞や体外循環時の血中脂肪酸増加する臨床条件を再現するためである。
註2．灌流遮断時間は通常20分〜30分で行われるが、本検証ではより条件を厳しくするために40分の灌流遮断時間を採用した。
(1-4)化合物の効果検証
(i)再灌流開始時に灌流液100ml中に検討化合物（各1mM）もしくは検討化合物無し(control、灌流液のみ)を投与し、acetyl-l-carnitine（1mM）およびdichloloacetate (1mM) 投与に対する心機能回復率と比較した。
(ii)検討化合物はKrebs-Henseleit緩衝液に溶解して調整した。
(1-5)虚血再灌流実験結果
検討化合物は、DCA(ジクロロ酢酸)、Acetyl-l- CA(アセチルカルニチン、図２-４では「acetyl-CA」と表示する)、compound2007-SA（図２、４では「SA」と表示する）, compound2007-amide, 3Cl-compound2007及び, 2Br-compound2007である。Controlは灌流液のみである。結果を以下の図１−４に示す。
Example 1
(1) Ischemic reperfusion experiment
(1-1) Animals used 6 weeks Splague-Dawley rat
(1-2) Isolated cardiac perfusion system: A cannula is inserted into the aorta and left atrium of the heart removed after general anesthesia, and then the perfusate is allowed to flow. The heart automatically beats and pumps perfusate. The pressure (= blood pressure), heart rate, and flow rate are measured and used as an index of cardiac function. The effects of ischemia and reperfusion were examined by blocking and resuming the perfusate.
(1-3) Perfusion conditions
(i) Perfusate: In Krebs-Henseleit buffer (NaCl; 118 mM, KCl; 4.7 mM, KH 2 PO 4 ; 1.2 mM, MgSO 4 · 7H 2 O; 1.2 mM, CaCl 2 · 2H 2 O; 1.25 mM) 5.5 mM glucose, 1.2 mM palmitic acid and 3% albumin were used.
(ii) The perfusate was oxygenated with 95% CO 2 + 5% O 2 gas.
(iii) Preperfusion was performed for 20 minutes → perfusion blockage for 40 minutes → reperfusion for 30 minutes.
註 1. Palmitic acid is added in order to reproduce the clinical conditions in which dysfunction during reperfusion increases in the presence of fatty acids and blood fatty acids increase during myocardial infarction and extracorporeal circulation.
註 2. The perfusion blocking time is usually 20 to 30 minutes, but in this verification, a 40 minute perfusion blocking time was adopted to make the conditions more strict.
(1-4) Verification of compound effects
(i) Cardiac function for administration of acetyl-l-carnitine (1mM) and dichloloacetate (1mM) after administration of study compound (1mM each) or no study compound (control, perfusion solution only) in 100ml of perfusate at the start of reperfusion Compared to recovery rate.
(ii) The study compound was prepared by dissolving in Krebs-Henseleit buffer.
(1-5) Results of ischemia / reperfusion experiment The compounds studied were DCA (dichloroacetic acid), Acetyl-l-CA (acetylcarnitine, shown as “acetyl-CA” in Fig. 2-4), compound2007-SA (Fig. 2 and 4 indicate “SA”), compound2007-amide, 3Cl-compound2007, and 2Br-compound2007. Control is only perfusate. The results are shown in FIGS. 1-4 below.
（２）compound2007 SAに対する毒性実験
(i) compound2007 SAをKrebs-Henseleit緩衝液で溶解し、50mg/kgを6週ラット（n=4）の腹腔内に投与した。
(ii) 投与後5日間経過観察を行い、全例生存していた。
(iii) Krebs-Henseleit緩衝液灌流液中にはcompound2007 SAを1.0mM（34.5mg）を添加している。
(iv) 中毒実験では、ラット体重は162g、156g、152g、162gで、ラットの血液循環量も大体体重の8%と考えると循環血液量は約12ml/150gで、compound2007 SA投与量は、50mg/kg=7.5mg/12mlと算出される。灌流は100mlで行っていたので、循環血液量を同じ100mlとすると、62.5mg/100mlとなり、腹腔内投与量は虚血再灌流心の1.0mMの投与量の約2倍であった。
(2) Toxicity experiment for compound2007 SA
(i) Compound 2007 SA was dissolved in Krebs-Henseleit buffer, and 50 mg / kg was intraperitoneally administered to rats (n = 4) for 6 weeks.
(ii) All patients were alive after 5 days of follow-up.
(iii) 1.0 mM (34.5 mg) of compound2007 SA is added to the Krebs-Henseleit buffer perfusate.
(iv) In the poisoning experiment, the rat body weight is 162g, 156g, 152g, 162g, and the blood circulation volume of the rat is also about 8% of the body weight, the circulation blood volume is about 12ml / 150g, the compound2007 SA dose is 50mg Calculated as /kg=7.5mg/12ml. Since the perfusion was performed at 100 ml, assuming that the circulating blood volume was the same 100 ml, the amount was 62.5 mg / 100 ml, and the intraperitoneal dose was about twice the 1.0 mM dose of the ischemia-reperfused heart.
Claims (7)
又はその塩。 Compound represented by the following formula (I)
Or a salt thereof.
で表される請求項１に記載の化合物又はその塩。 The following formula (IA)
The compound of Claim 1 represented by these, or its salt.
で表される請求項１又は２に記載の化合物又はその塩。 The following formula (IB)
The compound or its salt of Claim 1 or 2 represented by these.
The ischemic disease therapeutic agent according to claim 6, wherein the ischemic disease is ischemia reperfusion injury, myocardial infarction, cerebral infarction, distant organ injury or mesenteric vascular occlusion.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2015046825A JP6473352B2 (en) | 2015-03-10 | 2015-03-10 | Drug for ischemic disease |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2015046825A JP6473352B2 (en) | 2015-03-10 | 2015-03-10 | Drug for ischemic disease |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2016166148A JP2016166148A (en) | 2016-09-15 |
| JP6473352B2 true JP6473352B2 (en) | 2019-02-20 |
Family
ID=56897458
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2015046825A Active JP6473352B2 (en) | 2015-03-10 | 2015-03-10 | Drug for ischemic disease |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP6473352B2 (en) |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1156840B (en) * | 1978-06-27 | 1987-02-04 | Sigma Tau Ind Farmaceuti | ACIL DERIVATIVES OF CARNITINE |
| EP0177574B1 (en) * | 1984-04-02 | 1989-12-20 | Cornell Research Foundation, Inc. | Aminocarnitines |
| IT1299266B1 (en) * | 1998-05-15 | 2000-02-29 | Sigma Tau Ind Farmaceuti | REVERSIBLE CARNITINE PALMITOIL INHIBITORS TRANSFERRED |
| IT1317924B1 (en) * | 2000-10-31 | 2003-07-15 | Sigma Tau Ind Farmaceuti | SOLID COMPOSITIONS FOR ORAL ADMINISTRATION INCLUDING HYGROSCOPIC SALINONS OF L-CARNITINE AND ALCANOYL L-CARNITINE WITH |
| WO2007117544A2 (en) * | 2006-04-07 | 2007-10-18 | Ssv Therapeutics, Inc. | Carnitine conjugates of adamantanamines and neramexane derivatives as duel prodrugs for various uses |
| EP2299994A1 (en) * | 2008-06-16 | 2011-03-30 | Scian Laboratories, Llc | L-carnitine and alkanoyl l-carnitine phytates and process for preparing the same |
-
2015
- 2015-03-10 JP JP2015046825A patent/JP6473352B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| JP2016166148A (en) | 2016-09-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6685269B2 (en) | Method and apparatus for synthesizing contrast agents and intermediates thereof | |
| US11786501B2 (en) | Nitroxyl donors with improved therapeutic index | |
| JP2018048178A (en) | Oxabicycloheptanes, and oxabicycloheptanes for treatment of reperfusion injury | |
| JP2016128481A (en) | Nitroxyl donor for treating pulmonary hypertension | |
| JP2014500280A5 (en) | ||
| DERRICK et al. | Adjunctive use of a biologic pressor agent, angiotensin, in management of shock | |
| JP6473352B2 (en) | Drug for ischemic disease | |
| TW201010994A (en) | Use of soluble epoxide hydrolase inhibitors in the treatment of inflammatory vascular diseases | |
| PT2436672T (en) | Anti-shock agent comprising diaminotrifluoromethylpyridine derivative | |
| KR20160035061A (en) | Compound and methods for treating long qt syndrome | |
| JP4598674B2 (en) | Schizophrenia treatment | |
| KR101172472B1 (en) | Quaternary ammonium compound, process for producing the same, therapeutic agent for cerebrovascular disorder, and therapeutic agent for heart disease | |
| US20110144193A1 (en) | Pharmaceutical Composition Comprising Cinchonains Ia And Ib, Process For Preparing An Epimeric Mixture Of Cinchonains Ia And Ib, Use And Method For Reverting/Combating Ventricular Fibrillation | |
| RU2458690C1 (en) | 3-(2,2,2-trimethylhydrazinium) propionate-5-bromnicotinate 3-(2,2,2-trimethylhydrazinium) potassium propionate derivative exhibiting antiischemic activity | |
| JP3881061B2 (en) | Kidney disease prevention and treatment | |
| JP2001039874A (en) | Prophylactic and therapeutic agent for pulmonary hypeptension | |
| RU2458054C1 (en) | 3-(2,2,2-trimethylhydrazinium) propionate-nicotinate 3-(2,2,2-trimethylhydrazinium) potassium propionate derivative exhibiting antiischemic activity | |
| CN104755080A (en) | Otamixaban for use in the treatment of non-ST elevation acute coronary syndrome in patients planned to undergo coronary artery bypass grafting | |
| JP2006193494A (en) | Therapeutic agent for heart disease containing quaternary ammonium compound as active component | |
| BRPI0904460A2 (en) | pharmaceutical composition comprising cinchonain ia and ib, process for preparing an epimeric mixture of cinchonain ia and ib, use and method for reversing / combating ventricular fibrillation | |
| JPS6054360A (en) | 3-aryl-3-pyrroline derivative, manufacture and medicine composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180219 |
|
| A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20180220 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20180220 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20180927 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20181009 |
|
| A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20181203 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20190108 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20190125 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6473352 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |